The immune mechanisms that provide protection against malaria- associated disease and death remain poorly understood. In addition, the immune responses that contribute to protective immunity elicited by active vaccination in animal models of malaria are also poorly defined. Although elucidation of the exact mechanism(s) of immunity is not a prerequisite to the development of efficacious vaccines, in the absence of reliable in vitro correlates of protective immunity and with the lack of some understanding of what constitutes clinical immunity, development of effective malaria vaccines will continue to be empiric and haphazard at best. The major goals of this project are to clearly define the basis of protective immunity that develops after vaccination with subunit asexual blood stage vaccines in experimental animal models and develop relevant biological assays that will assist in the evaluation of candidate asexual blood stage malaria vaccines in humans. In addition, in the absence of either of the above, we are also taking an empiric approach to human vaccine development in the Aotus-P. falciparum monkey model. We have now established that protective immunity can be elicited routinely by subunit vaccination with the merozoite Major Surface Protein 1 MSP1) in both murine (Plasmodium yoelii in mice) and primate (P. falciparum in Aotus monkeys) malaria models. The central role of antibodies has been clearly established, but the contribution of other humoral and cellular components of the immune system remain to be determined.